Breakthrough drug changes outlook for tuberous sclerosis

Research at Cincinnati Children’s played major role in FDA approval for everolimus

For nearly 50,000 children and adults in the United States who live with tuberous sclerosis complex (TSC), April 30, 2012, was a big day.

That was the day the US Food and Drug Administration (FDA) approved the drug everolimus as the first medication that can shrink the non-cancerous kidney tumors that strike up to 80 percent of people with this inherited condition. The newly approved drug will allow many patients to maintain kidney function for years to come – without the need for repeated surgical intervention.

“Not every patient will need this drug, and not every patient who takes the drug will have the same experience. But this is the first drug we’ve had that can alter the course of this disease,” says John Bissler, MD, a nephrologist and researcher at Cincinnati Children’s whose clinic treats more than 700 TSC patients – the largest of its kind worldwide. “This drug has the potential of taking patients out of the danger zone and keeping them out of the hospital.”

Taming tumor growth

Tuberous sclerosis is a genetic disorder that causes non-cancerous tumors to form in the brain, eyes, heart, kidneys, skin and lungs. Worldwide, an estimated 1 million people have TSC.

In the kidneys, TSC tumors can damage organ function as they grow, which can lead in some cases to dialysis and the need for organ transplantation. More commonly, the irregular blood vessels inside these tumors can form dangerous aneurysms that require treatment to prevent internal bleeding.

For years, the only available treatments for renal angiomyolipomata have been surgical: including full nephrectomies, partial nephrectomies and catheter-based arterial embolization procedures. Now there is a new option.

Cincinnati research plays key role

Studies in the 1990s traced the roots of TSC to defects in two genes: TSC1 and TSC2. When these genes malfunction, the body produces higher levels of mTOR, a protein known to trigger uncontrolled tumor cell and blood vessel growth.

These findings led to a hunt for an mTOR inhibiting drug. Everolimus, a medication made by Novartis and already approved as an anti-rejection agent in organ transplants, emerged as the prime candidate.

At Cincinnati Children’s research efforts have been led by Bissler, Frank McCormack, MD an adult Pulmonologist, and David Franz, MD, a neurologist here who started the Cincinnati TSC Clinic.

In 2008, Bissler was lead and McCormack and Franz were senior authors on an 18-patient proof-of-concept study, published in the New England Journal of Medicine (NEJM), that demonstrated the potential for using everolimus as a TSC treatment for the renal tumors and a lung disease called lymphangioleiomyomatosis (LAM) affecting about 35 percent of women.

Franz was senior author for another paper, published in 2010 in the NEJM, that demonstrated the drug’s ability to reduce seizures and shrink brain tumors called subependymal giant cell astrocytomas (SEGAs) in children with tuberous sclerosis. The FDA approved everolimus for treating TSC-related brain tumors based on work done in Cincinnati.

In 2011, McCormack published confirmation that such a drug also can improve LAM.

Meanwhile, Bissler helped design Novartis’ EXIST-2 study, a 118-patient Phase III clinical trial that led to the recent FDA approval. The EXIST-2 trial reported that 42 percent of treated patients experienced at least a 50 percent reduction in kidney tumor size that lasted at least three months, while no tumor shrinkage occurred among those receiving placebo.

How long the tumor reduction may last remains under investigation. Novartis is sponsoring a four-year follow-up study to track longer-term effects. Research continues at Cincinnati Children’s, and elsewhere, to measure the effects of mTOR inhibitors on skin lesions, neurocognitive effects and other problems that strike TSC patients.

Who should get the drug?

Patients and families from as far as Portugal already have contacted the TSC Clinic at Cincinnati Children’s to inquire about everolimus. Bissler is working with a physician in England to draft guidelines for when and how to prescribe this new drug.

“The health effects experienced by tuberous sclerosis patients are highly variable. It’s important for these patients to be cared for at an experienced treatment center,” Bissler says.